Heretofore, there has been a need for an efficient process for the production of 3-fluorosalicylaldehyde which is necessary to the preparation of fluomine [cobalt bis (3-fluorosalicylaldehyde)-ethylenediimine], useful for the chelation of oxygen in aerospace applications. 3-Fluorosalicylaldehyde has proven to be extremely difficult to prepare in more than small laboratory quantitites in the past since each position ortho to the ring hydroxyl group is substituted. The presence of the strongly electronegative fluorine atom which blocks one of the ortho positions tends to deactivate the remaining ortho position so that the para-isomer (3-fluoro-4-hydroxybenzaldehyde) is formed preferentially. Prior processes for the preparation of 3-fluorosalicylaldehyde have tended to be highly time-consuming and are characterized by low overall yields.
The only practical starting material for the preparation of 3-fluorosalicylaldehyde is ortho-fluorophenol, although a seven step process starting with 2-amino-4-chloroanisole has been reported (U.S. Pat. Nos. 2,576,064; 2,576,065; 2,590,813; and 2,676,189.
The direct preparation using the conventional Reimer-Tiemann reaction for the synthesis of salicylaldehydes, although having the advantage of extreme simplicity, has not proven to be practical since yields of the ortho-isomer were generally less than 7 percent, the bulk of the phenol having been converted to the para-isomer. It should be noted that the conventional Reimer-Tiemann reaction is conducted in an aqueous system.
The Kolbe-Schmidt reaction, involving the carboxylation of an alkali salt of o-fluorophenol with carbon dioxide under pressure, gives both the ortho and para-isomers of the acid. The mixture of acids can be reduced by sodium amalgam to the corresponding aldehydes, separation of the aldehydes then being effected by azeotropic distillation of the desired 3-fluorosalicylaldehyde. It is necessary to use a primary amine such as p-toluidine to stop the reduction at the aldehyde stage and prevent further reduction to the alcohol. This procedure was utilized by Melvin Calvin and his coworkers at the University of California at Berkeley for the initial bulk preparations of 3-fluorosalicylaldehyde during the 1940's (see U.S. Pat. No. 2,493,654).
The initial preparation of 3-fluorosalicylalcohol, followed by subsequent oxidation to the desired 3-fluorosalicylaldehyde, has also been reported (U.S. Pat. No. 3,780,110). This involves the reaction of o-fluorophenol with trioxane utilizing the technique disclosed by Marchand and Grenet (U.S. Pat. No. 3,290,393) in which the phenoxyboroxine is prepared initially so as to reduce resin formation. This synthesis also requires the use of p-toluidine (or other primary amine) during the oxidation so as to stop the oxidation at the aldehyde stage.
Both the acid and alcohol routes are time consuming, result in relatively low overall yields, and require involved purification steps since it is necessary to eliminate all traces of p-toluidine from the 3-fluorosalicylaldehyde, such primary amines having been found to deactivate the fluomine which is the desired final product.
It has now been found that the Reimer-Tiemann reaction will take place in hydrocarbon diluents under essentially anhydrous conditions if the reaction is catalyzed by an aprotic solvent such as N,N-dimethylformamide. A completely anhydrous reaction is not possible since water forms during the reaction but this can be effectively removed by the use of excess sodium hydroxide (solid). Using the anhydrous Reimer-Tiemann process, yields of 12.5 to 15 percent have been consistently obtained even when scaled-up. Recovery and recycle of unreacted phenol indicates overall yields should approach 50%. The simiplicity and rapidity of the conventional Reimer-Tiemann synthesis is maintained, with the exception that an extraction step is required.
In additon, an improved method for separation of the unreacted o-fluorophenol from the desired 3-fluorosalicylaldehyde has been developed so that the overall manufacturing time is completely minimized. No primary amines are required during the recovery phase so that no possible contamination of the final product is possible. The only by-products found have been a minimal quantity of black tar (soluble in acetone) and a white powder (m.p. in excess of 170.degree.C) which azeotropes with difficulty during the distillation stage. It has been determined that this white powder does not affect the activity of fluomine. The process seems to be selective for formation of the ortho-isomer (salicylaldehyde) since no para-isomer has been found.
It is an object of the present invention to provide an improved process for the synthesis of salicylaldehydes from phenolic starting materials.
It is an object of the present invention to provide an improved process for the direct preparation of 3-substituted salicyladehydes (e.g. 3-fluorosaliclaldehyde), using the reactants and simplicity inherent in the classical Reimer-Tiemann synthesis, by modification of this synthesis so that the reaction takes place under essentially anhydrous conditions, the water of reaction being taken up by an excess of sodium hydroxide or other dehydrating agent. The reaction proceeds in a hydrocarbon diluent such as benzene when it is catalyzed by a solvent such as N,N-dimethylformamide.
It is a further object of the present invention to provide a process for the preparation of 3-fluorosalicylaldehyde on a more efficient basis and in greater overall yield than, heretofore, generally was possible in the prior art.
It is an object of the present invention to provide an improved route for the direct preparation of 3-fluorosalicylaldehyde with minimum formation of the unwanted para-isomer and other undersirable by-products and tars.
It is another object of the present invention to provide an improved process for the expeditious synthesis of 3-fluorosalicylaldehyde wherein the overall reaction and recovery time is accelerated when compared with processes of the prior art.
It is an object of the present invention to provide an improved method for recovery and purification of the desired 3-fluorosalicylaldehyde from the reaction step.
It is an object of the present invention to provide an improved route for the production, recovery and purification of 3-fluorosalicylaldehyde in the absence of any chemical agents (such as p-toluidine) which could subsequently contaminate and deactivate the fluomine prepared therefrom.
It is another object of the present invention to provide an improved process for the synthesis of 3-fluorosalicylaldehyde which is amenable to large scale implementation.
These and other objects, as well as the scope, nature and utilization of the process, will be apparent from the following detailed description and appended claims.